Clinico-laboratory Hallmarks and Management Approaches in Relapsed and Refractory Chronic Myeloid Leukemia

Background: The clinico-evolutional, hematological and molecular-cytogenetic patterns of chronic myeloid leukemia (CML) comprise splenomegaly, myeloid hyperplasia of the bone marrow, hypercatabolic symptoms, balanced genetic translocation [t(9;22)(q34;q11.2)] and tyrosine kinase (TK) activity of the oncogenic proteins encoded by BCR-ABL transcripts, being characterized in the accelerated and acute phases by the relapsing disease course and unfavorable prognosis, with negative socio-economic impact. The biological significance of lactate dehydrogenase (LDH), T315I and K222R/665A mutations of BCR-ABL1 gene are continuously researching in relapsed and refractory cases in order to optimize the therapeutic approaches overcoming resistance to tyrosine kinase inhibitors (TKIs).

The objective of our study was to assess the biological significance of lactate dehydrogenase (LDH), T315I and K222R/665A mutations and their impact on treatment options in newly diagnosed and relapsed patients with CML.

Material and Methods: Our analytical, cross-sectional, observational and descriptive studies enrolled 32 patients with different phases of CML, who were followed up and treated at the Institute of Oncology from Moldova between 1995-2022. Venous blood samples were collected for LDH assay, molecular screening and detection of T315I and K222R/665A mutations of the BCR-ABL1 gene in order to evaluate the biological significance of the increased LDH values and mutational burden. CML patients underwent chemotherapy with alkylating agents, antimetabolites and TKIs. While doing the qualitative research, a narrative synthesis of the literature data has been performed.

Results: The patient age ranged from 20 to 67 years (average 52.6±2,14 years). The diagnosis of CML was established in the late chronic phase in 30 (93.8%) patients. The quantitative real-time PCR revealed p210 transcript of BCR-ABL chimeric gene in all cases, with the range of 21-100% and median value of 74.63±3.19%. LDH at diagnosis ranged between 169-2429 U/L and was increased in 20 (62.5%) patients, especially in those with leukocytosis over 100x109/l. The complete cytogenetic and complete or major molecular responses were recorded under treatment with different generations of TKIs in 23 (71.9%) cases, including 4 cases with T315I mutation. Relapses occurred in 11 (55.0%) patients with initially increased LDH values, in 6 (60%) of 10 patients with T315I mutation and in one case with K222R/665A mutation. One (3.7%) patient with the initially elevated LDH level and T315I mutation evolved into the acute phase disease, and achieved only the partial hematological response after treatment with ponatinib, a 3rd generation TKI. The survival of patients from the disease onset till the last monitoring visit ranged between 32 and 246 months (median 97.82±4.51).

Conclusions: The increased LDH values may suggest the activity of CML at diagnosis and in relapse. In our study T315I and K222R/665A mutations of BCR-ABL1 gene and the increased values of LDH were associated with a higher relapse rate and resistance to imatinib mesylate. TKIs improve considerably the survival and ECOG-WHO score of CML patients regardless of the treatment line, as well as in relapses.